Polyamine-Activated Carbonyl Stress Nanoplatform Synergistically Reverses Biofilm-Driven Immunosuppressive Microenvironment

Abstract

Polyamine metabolic dysregulation induced by implant-associated infections (IAIs) is a pivotal contributor to the formation of an immunosuppressive microenvironment. Excessive polyamines facilitate pathogen persistence by suppressing bacterial membrane lipid peroxidation (LPO) and enhancing DNA repair mechanisms. Simultaneously, polyamines promote biofilm formation via quorum sensing (QS) modulation and inhibit host immunity to facilitate immune escape. Herein, we developed a polyamine-responsive carbonyl stress nanoplatform MIL-100@PAO@PVP (MPP), which synergistically integrates metabolic intervention and chemodynamic therapy (CDT), addressing the limitations inherent to conventional oxidative damage-based therapies. Specifically, plasma amine oxidase (PAO) within MPP catalyzes polyamine degradation at infection sites, generating highly toxic acrolein and hydrogen peroxide (H₂O₂). The produced H₂O₂ markedly enhances MIL-100-mediated CDT, triggering a burst of hydroxyl radicals (^•OH) that induces severe bacterial membrane LPO and DNA damage. Importantly, the generated acrolein further amplifies bacterial DNA damage via the induction of carbonyl stress. Additionally, bacterial debris resulting from MPP-induced cell death acts as endogenous antigens, effectively activating the antigen-presenting functions of macrophages and dendritic cells (DCs), thus reshaping the local immune response and reversing immunosuppression. Experimental results demonstrated robust antibiofilm efficacy and immunostimulatory effects of MPP in both in vitro and in vivo models, highlighting a promising therapeutic strategy for treating IAIs.